title: Binding mechanism and synergetic effects of xanthone derivatives as noncompetitive α-glucosidase inhibitors: a theoretical and experimental study.
abstract: Newly emerged xanthone derivatives have attracted considerable interests as a novel class of potent α-glucosidase inhibitors. To provide insights into the inhibitory and binding mechanisms of xanthone-based inhibitors toward α-glucosidase, we carried out experimental and theoretical studies on two typical xanthone derivatives, i.e., 1,3,7-trihydroxyxanthone and 1,3-dihydroxybenzoxanthone. The results indicate that these two xanthone derivatives belong to noncompetitive inhibitors and induce a loss in the α-helix content of the secondary structure of α-glucosidase. Docking simulation revealed the existence of multiple binding modes, in which polyhydroxyl groups and expanded aromatic rings acted as two key pharmacophores to form H-bonding and π-π stacking interactions with α-glucosidase. The fact that 1,3,7-tridroxyxanthone and 1,3-dihydroxybenzoxanthone exhibited significant synergetic inhibition to α-glucosidase strongly suggests that both xanthone derivatives simultaneously bind to the distinct noncompetitive sites of yeast's α-glucosidase. On the basis of the plausible binding clues, synergetic inhibition can be developed to be a promising strategy to achieve enhanced inhibitory activities.
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry/KLGHEI of Environment and Energy Chemistry, School of Chemistry & Chemical Engineering, Sun Yat-sen University , Guangzhou 510275, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.forename: Wen-Hua
authors.initials: WH
authors.lastname: Chen
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.forename: Zhuofeng
authors.initials: Z
authors.lastname: Ke
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*; D000520:alpha-Glucosidases / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D044004:Xanthones; D000520:alpha-Glucosidases